Flavonoids isolated from Citrus platymamma induce mitochondrial-dependent apoptosis in AGS cells by modulation of the PI3K/AKT and MAPK pathways

Oncol Rep. 2015 Sep;34(3):1517-25. doi: 10.3892/or.2015.4122. Epub 2015 Jul 10.

Abstract

Citrus platymamma hort. ex Tanaka (Rutaceae family) has been widely used in Korean folk medicine for its wide range of medicinal benefits including an anticancer effect. In the present study, we aimed to investigate the molecular mechanism of the anticancer effects of flavonoids isolated from Citrus platymamma (FCP) on AGS cells. FCP treatment significantly inhibited AGS cell growth in a dose‑dependent manner. Furthermore, FCP significantly increased the percentage of cells in the sub-G1 phase (apoptotic cell population), and apoptosis was confirmed by Annexin V double staining. Chromatin condensation and apoptotic bodies were also noted in the FCP-treated AGS cells. Moreover, immunoblotting results showed that FCP treatment significantly decreased the expression of procaspase-3, -6, -8 and -9, and PARP and increased cleaved caspase-3, cleaved PARP and the Bax/Bcl-xL ratio in a dose-dependent manner. In addition, the phosphorylation of AKT was significantly decreased, whereas extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) were significantly increased in the FCP-treated AGS cells. Taken together, the cell death of AGS cells in response to FCP was mitochondrial-dependent via modulation of the PI3K/AKT and MAPK pathways. These findings provide new insight for understanding the mechanism of the anticancer effects of FCP. Thus, FCP may be a potential chemotherapeutic agent for the treatment of gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Citrus / chemistry
  • Flavonoids / administration & dosage*
  • Flavonoids / chemistry
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mitochondria / drug effects
  • Mitogen-Activated Protein Kinase Kinases / biosynthesis
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Neoplasm Proteins / biosynthesis*
  • Oncogene Protein v-akt / genetics
  • Phosphatidylinositol 3-Kinases / biosynthesis
  • Phosphatidylinositol 3-Kinases / genetics
  • Signal Transduction / drug effects
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / pathology

Substances

  • Flavonoids
  • Neoplasm Proteins
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt
  • Mitogen-Activated Protein Kinase Kinases